Effects of Low-level Persistent Infection on maintenance of immunity by CD4 T cell subsets and Th1 cytokines

Abstract

CD4 T cells are required, along with antibodies, for complete protection from blood-stage infection with Plasmodium spp., which cause malaria. Without continuous exposure, as on emigration of people from endemic areas, protection from malaria decays. As in other persistent infections, low-level P. chabaudi protects the host from re-infection at two months post-infection, a phenomenon termed premunition. Premunition is correlated with T cell responses, rather than antibody levels. We previously showed that while both effector T cells (Teff) and memory T cells (Tmem) are present after infection, Teff protect better than Tmem. Here we studied T cell kinetics post-infection by labelling dividingIfng+T cells with BrdU in infectedIfng-reporter mice. A large drop in specific T cell numbers andIfng+cells upon clearance of parasite suggest a mechanism for decay of protection. Although protection decays, CD4 Tmem persist, including a highly-differentiated CD27−Effector Memory (Tem) subset that maintains someIfngexpression. In addition, pre-treatment of chronically-infected animals with neutralizing antibody to IFN-γ, or clodronate liposomes before re-infection decrease premunition supporting a role for Th1-type immunity to re-infection. A pulse/chase experiment comparing chronically infected to treated animals showed that recently dividedIfng+T cells, particularly IFN-γ+TNF+IL-2−T cells, are promoted by persistent infection. These data suggest that low-level persistent infection reduces CD4+Tmem survival and multi-functional Teff but promotes IFN-γ+TNF+IL-2−Late Effector Memory and Terminally Differentiated Effector T cells and prolongs immunity.

Boosting Live Malaria Vaccine with Cytomegalovirus Vector Can Prolong Immunity through Innate and Adaptive Mechanisms

“…IFN-γ production has been previously reported in MCMV and HCMV infection during the period coinciding with latency [23]. Data from our laboratory and others establishes that IFN-γ expression during persistent P. chabaudi infection, or recombinant IFN-γ also promote protection from heterologous re-infection at day 200 [12,44]. It was also reported that rIFN-γ increased the number of polyclonal Tem at day 200 after P. chabaudi infection [44].…”

“…To test the potential of an MCMV-based booster vaccine, mice were vaccinated with live P. chabaudi AS infection followed by sub-curative doses of chloroquine and then boosted with MCMV-BAC or MCMV-B5 140 days later, as schematically depicted in Fig 3A . As vaccineinduced protection decays by day 200, we tested MCMV boosters for protection from heterologous re-infection with P. chabaudi AJ at day 200, which corresponds to 60 days after boosting. This timing was chosen on the basis that neither immunity nor the T cell response to live vaccination has completely decayed by day 120 [3,12], and that the MCMV infection is below detectable by day 60 [24], though we expected it to show prolonged stimulatory capacity at this timepoint [22].…”

“…The copyright holder for this preprint (which this version posted May 2, 2023. ; https://doi.org /10.1101/2023.05.02.539025 doi: bioRxiv preprint 5 is transient and not present on Tem, we were able to determine that adoptively transferred Teff are the most protective T cells in systemic, blood-stage P. chabaudi infection [8,10]. However, shortlived CD4 T cell immunity has been identified as the crucial variable resulting in short-term protection from persistent P. chabaudi infection or vaccination [3,12]. However, standard vaccines do not generate durable Teff responses, leading to the problem at hand of what vaccine vector to use to prolong protection, if the cell type that protects is short-lived.…”